Phenyl carbamates of aminopropanediols



Patented June 11,1935

; UN T PATENT orries 12,004,132; r v PHENYL' CARBAMATES OF AIHINOPRO K PANEDIOLS Theodore H. Rider, Cincinnati, out

No'DrawingrApplication Anglia 10, 1931. Serial no. 556,331

. 11 Claims (attics- 4s The present'invention relates-to the production of the salts of gamma-dialkyl amino propanediol esters of aromatic carbamic acids which possess the general formula 3 0 ox R.

ArNH OOH-(!ZHQHa-.I- LHA l in which R and R" represent alkyl radicals which may be either alike or different or in'which the grouping may represent a .heterocyclic ring attached through nitrogen (such as the piperidine ring) in which Ar representsan aromatic group such as a phenyl group or a substituted phenyl group, in which .H.A represents any highly ionized mineral acid, and in whichX represents hydrogen or anacylradical. V

General methodof synthesizing compound-sci this series Phenyl isocyanate (or other aromatic or substituted aromatic isocyanate or one of the corresponding carbamyl chlorides) is added to an equal molecular quantity of a dialkylamino propanediol in ether as a solvent The mixture is heated for a short time to insure completion of the reaction. The formation of the ester linkage is completed at this point and the probable formula as follows:

'-o 3011 V 1 1 Ar-NH- -p oHr-oH-orrr-N V I 7 R" It is possible to isolate the ester at this point;

but it is preferable to prepare a saltbyadding.

an acid to the ether. solution. In such-manner the hydrochloride of the ester is precipitated by passingdry' gaseous hydrogen chloride into the reaction mixture. The precipitated hydroch1oride (frequently. an oil) is separated by decantation and recrystallized from a mixture of ethyl acetate and acetone. The salt precipitated at this point :has aprobableformula as follows:

0 OH R It is especially to be noted that the ester con tai'ning the free.hydroxylgroup prepared as just resultant compound has a described (the mono-ester in which the X in the first formula .represents hydrogen) is easily destroyed by alkali, so that it is not feasible to isolate it according to the procedure, usual in other cases, of dissolving the hydrochloride in water and 5 throwing out the free base by adding alkali.

The mono-.ester may be further reacted with other acid chlorides or'isocyanates torgive simple or mixed esters. Where a simple di-ester (i. e. where X represents a carbamyl radical, both ester 10 groupingsbeing identical). is desired, it is simpler to react the dialkylamino propanediol with two molecular quantities of phenyl 'isocyanate (or otherisocyanate or acid chloride). This reaction is carried o'utin a manner similar to that de- 5 scribed above for the preparation of the monoester. e probable formulafor such a di-ester is'a'sfollowsz "ff v v This ester may be isolated as such or its. salts may be formed directly as described above for the mono-ester. In the case of the di-ester, it is more feasible to isolate the free base by adding alkali to an aqueous solution of the hydrochloride. Both types of esters possess anesthetic properties.

7 Specific compoundeinthe mono-ester series r The ether-layer is-then decantedbif and there- 50 mai'ningoil'yproduct is dissolved in a hot mixture bfacetone and ethyl acetate which on cooling precipitates white crystalsof thehydrochloride 0f'the mono phenyl urethane of gamma-di-nbutyl amino propanediol, melting at:128 129=C.

2 The product is a local anesthetic. Following the specific directions just mentioned, the following additional compounds have been prepared, the probable formulas of which are indicated.

The hydrochloride of the mono phenyl urethane of di-methyl amino propanediol, white crystals,

the hydrochloride of the mono phenyl urethane of di-ethyl amino propanediol,. white .cryistals', M. P. 135; I

HECIH! the hydrochloride of the mono phenyl urethane of di-n-propylamino propanediol, white crystals, M ;P..163-l6l4.; on uni- 01350113 v cflns-Nn-tl-oom-cfiom-n 11101 lagers-r0113 the hydrochloride of. the mono phenyl urethane of, diaisobutyl amino propanediol, "white crystals, M.P.12'5-12'7; I i

V the hydrochloride of the mono hnyiluremahe of. di-n-amylamino propanediol, white crystals, M. P. 101-103";

I CHDPCH: cunrNn c-oon -tn-omels 7, H01

7 V I GfiDr-CH:

and the hydrochloride of the mono phenyl ure thane of piperidino propanediol, "white crystals, M.'P. "rm-177 ,0 011 g C FQH, oum nfiia-wcngbir-on ii f ore-H01 (um-on,"

These compounds may :also be-obtained .as salts of nitric, sulfuric and other acids, bothinorganic and organic.

Specific compounds inathe diwster series A specific compound "belonging ito'ithe lgeneral series of di-esters as above.defined is .the hydrochloride of the di-phenyl'urethane of gammapiperidino propanediol scribed above. I,n cc; of anhydrous-ether 15.0 ;g.fof :phenyLisocyanate areaadded to 10; g. of piperidino ,propanediol; aand the solution f'boiled for :two :hours, after-which it is :cooled andIsat'ue rated with dry hydrogenchloridecgas; The ether .ethyl amino propanediol, 109

layer is then decanted off and the remaining insoluble product is dissolved in a hot mixture of acetone and ethyl acetate which on'co-oling precipitates White crystals of the hydrochloride of the di-phenylurethane of gamma-piperidino propanediol, melting at 197-198 C. Following the specific directions just mentioned the following additional. compounds have been prepared, the probable formulas of which are'indicated. The hydrochloride of the diphenyl urethane of dithe hydrochloride of the di-pheny1 urethane of di-n-propyl amino propanediol, white crystals, M;I!.:183-188 V r I :cmomom C1H5NH'G''-0OHF iI-om-N n01 CH2.0H2.CH3

the l 13 ;.11'662111orid e of the diphenyl urethane of di-isobutylamin-o propanediol, white crystals, M. P. 116-118;

The scope-of the invention should be determined by :the language of the appended claims, :which should I be Jinterpretedas broadly :as possible con sistent-withtheistate:ofthe art.

Whatiis 'claimedis:

1. The hydrochloride of ,a gamma dialkylamino propanediol ester of an aromatic carbamic acid possessing thegeneral structure 7 o I on v ir-NH-{-OCE-lE-OHFN HOl Ii in Whichlt' mm" represent alkyl radicals, and in which Ar represents a radical of the benzene series. 7. 2; The hydrochloride Of xaggamma, dialykle white crystals, M. P.

amino propanediol ester of an aromatic carbamic acid possessing the general structure in which R and R represent a pentamethylene chain both ends of which are attached to the N atom, and in which Ar represents a radical of the benzene series.

3. The hydrochloride of a gamma dialkylamino propanediol ester of an aromatic carbamic acid possessing the general structure in which R and R represent alkyl radicals or in which R and R together may represent a pentamethylene chain both ends of which are attached to the N atom, in which Ar represents a radical of the benzene series, and in which the hydrogen of the hydroxyl group may be esterified with an aryl carbamic acid of the benzene series, the balance of the compound being unchanged.

7. The hydrochloride of a gamma di-alkyl amino propanediol ester of an aromatic carbamic acid possessing the general structure in which R and R" represent alkyl radicals or in which R and R together represent a pentam'ethylene chain both ends of which are attached to the N atom, in which Ar represents a radical of the benzene series, and in which the hydrogen of the hydroxyl group may be esterified with an aryl carbamic acid of the benzene series, the balance of the compound being unchanged.

8. The hydrochloride of a gamma-dialkyl amino propanediol ester of an aromatic oarbamic acid possessing the general structure:

0 Asn-tL-o OH:

, R! in which R and R" represent alkyl radicals or in which R and R" together represent a pentamethylene chain both ends of which are attached to the N atom, and in which Ar represents a radical of the benzene series.

9. A compound of the general series O Ar-NH-L-O H H OX Ar-NH-O-O OHPH-OHPN -HA in which R and R represent alkyl radicals or in which R and R. together represent a pentamethylene chain both ends of which are attached to the N atom, in which Ar represents a radical of the benzene series, in which X represents hydrogen or an aryl carbamyl radical of the benzene series and in which HA represents a highly ionized mineral acid.

10. A compound of the general series 7 o ox R Ar-Nn- -o OHrH-CH2N I in which R and R represent a pentamethylene chain both ends of which are attached to the N atom, in which Ar represents a radical of the benzene series, in which X represents hydrogen or an aryl carbamyl radical of the benzene series and in which HA represents a highly ionized mineral acid.

11. A jmbnophenyl urethane of a gamma aminopropanediol possessing the general structure V in which R and R represent alkyl radicals or in which R and R together will be a pentamethylene chain both ends of which are attached to the N atom, in which Ar represents a radical of the benzene series, this compound existing in an organic solvent in substantially pure state when prepared as described and being in this state capable of having its free hydroxyl group acted upon by compounds of an acidic nature in order to prepare di-esters.

THEODORE H. RIDER. 

